Evolving concepts on bradykinesia Bologna, Matteo; Paparella, Giulia; Fasano, Alfonso ...
Brain,
03/2020, Volume:
143, Issue:
3
Journal Article
Peer reviewed
Open access
Bradykinesia is one of the cardinal motor symptoms of Parkinson's disease and other parkinsonisms. The various clinical aspects related to bradykinesia and the pathophysiological mechanisms ...underlying bradykinesia are, however, still unclear. In this article, we review clinical and experimental studies on bradykinesia performed in patients with Parkinson's disease and atypical parkinsonism. We also review studies on animal experiments dealing with pathophysiological aspects of the parkinsonian state. In Parkinson's disease, bradykinesia is characterized by slowness, the reduced amplitude of movement, and sequence effect. These features are also present in atypical parkinsonisms, but the sequence effect is not common. Levodopa therapy improves bradykinesia, but treatment variably affects the bradykinesia features and does not significantly modify the sequence effect. Findings from animal and patients demonstrate the role of the basal ganglia and other interconnected structures, such as the primary motor cortex and cerebellum, as well as the contribution of abnormal sensorimotor processing. Bradykinesia should be interpreted as arising from network dysfunction. A better understanding of bradykinesia pathophysiology will serve as the new starting point for clinical and experimental purposes.
Key points
We explored the large variability in motor skill acquisition‐related effects on the primary and sensory cortices. Namely, we tested whether this variability depends on interindividual ...variance or the type of motor task investigated.
We compared different motor‐learning tasks, i.e. model‐free vs. model‐based learning tasks, and their possible differential effects on the primary motor and sensory cortices by using transcranial magnetic stimulation techniques.
The model‐free learning task induced an increase in corticospinal excitability and a reduction in the amplitude of somatosensory‐evoked potentials. Conversely, the model‐based learning tasks induced a decrease in intracortical inhibition.
No correlations were found between neurophysiological changes and motor performance, indicating that this differential modulation may be secondary to the motor skill acquisition.
The study results suggest differential motor skill acquisition‐related effects on cortical parameters, possibly due to the engagement of specific neurophysiological substrates.
A large variability in learning‐related neurophysiological changes in the primary motor and sensory cortices has been observed. It is unclear whether these differential effects are due to the different tasks investigated or to interindividual variance. Only a few studies have assessed different motor‐learning tasks and their effects on neurophysiological features within the same group of participants, and several issues are unclear. Here, we compared the effects of different tasks within each individual. We investigated the effects on motor and sensory cortex parameters after a model‐free learning task, i.e. a ballistic motor task, compared with model‐based learning tasks, i.e. visuomotor‐learning tasks. Motor‐ and sensory‐evoked potentials, intracortical excitability as assessed by short‐interval intracortical inhibition, and sensorimotor interaction, i.e. short‐latency afferent inhibition, were recorded from 15 healthy subjects before and after the tasks. The ballistic motor task induced an increase in corticospinal excitability but did not change motor cortex intracortical inhibition or sensorimotor integration. In addition, it decreased the amplitude of cortical components of the somatosensory‐evoked potentials. The visuomotor‐learning tasks induced a reduction in motor cortex intracortical inhibition but did not modulate corticospinal and sensory cortex excitability or sensorimotor integration. This differential modulation is likely to be secondary to the motor skill acquisition, since no correlation was observed between neurophysiological changes and motor performance. Our results demonstrate differential motor skill acquisition‐related effects on cortical parameters, possibly reflecting the engagement of specific neurophysiological substrates, and contribute in‐depth knowledge of the mechanisms involved in different types of motor skill acquisition in humans.
Key points
We explored the large variability in motor skill acquisition‐related effects on the primary and sensory cortices. Namely, we tested whether this variability depends on interindividual variance or the type of motor task investigated.
We compared different motor‐learning tasks, i.e. model‐free vs. model‐based learning tasks, and their possible differential effects on the primary motor and sensory cortices by using transcranial magnetic stimulation techniques.
The model‐free learning task induced an increase in corticospinal excitability and a reduction in the amplitude of somatosensory‐evoked potentials. Conversely, the model‐based learning tasks induced a decrease in intracortical inhibition.
No correlations were found between neurophysiological changes and motor performance, indicating that this differential modulation may be secondary to the motor skill acquisition.
The study results suggest differential motor skill acquisition‐related effects on cortical parameters, possibly due to the engagement of specific neurophysiological substrates.
In humans, gamma (γ) oscillations in cortical motor areas reflect asynchronous synaptic activity and contribute to plasticity processes. In Parkinson's disease (PD), γ oscillatory activity in the ...basal ganglia-thalamo-cortical network is altered and the long-term potentiation (LTP)-like plasticity elicited by intermittent theta burst stimulation (iTBS) is reduced in the primary motor cortex (M1). In this study, we tested whether transcranial alternating current stimulation (tACS) delivered at γ frequency promotes iTBS-induced LTP-like plasticity in M1 in PD patients. Sixteen patients ('OFF' condition) and 16 healthy subjects (HS) underwent iTBS during γ-tACS (iTBS-γ tACS) and during sham-tACS (iTBS-sham tACS) in two sessions. Motor-evoked potentials (MEPs) evoked by single-pulse TMS and short-interval intracortical inhibition (SICI) were recorded before and after the co-stimulation. A subgroup of patients also underwent iTBS during β tACS. iTBS-sham tACS facilitated single-pulse MEPs in HS, but not in patients. iTBS-γ tACS induced a larger MEPs facilitation than iTBS-sham tACS in both groups, with similar values in patients and HS. In patients, SICI improved after iTBS-γ tACS. The effect produced by iTBS-γ tACS on single-pulse MEPs correlated with disease duration, while changes in SICI correlated with UPDRS-III scores. The effect of iTBS-β tACS on both single-pulse MEPs and SICI was similar to that obtained in the iTBS-sham tACS session. Our data suggest that γ oscillations have a role in the pathophysiology of the abnormal LTP-like plasticity in PD. Entraining M1 neurons at the γ rhythm through tACS may be an effective method to restore impaired plasticity.
In Parkinson's disease, the LTP-like plasticity of the primary motor cortex is impaired, and gamma oscillations are altered in the basal ganglia-thalamo-cortical network. Using a combined TMS-tACS approach (iTBS-γ tACS co-stimulation), we demonstrate that driving gamma oscillations restores the LTP-like plasticity in patients with Parkinson's disease. The effects correlate with clinical characteristics of patients, being more evident in less affected patients and weaker in patients with longer disease duration. These findings suggest that cortical gamma oscillations play a beneficial role in modulating the LTP-like plasticity of M1 in Parkinson's disease. The iTBS-γ tACS approach may be potentially useful in rehabilitative settings in patients.
Whether neurophysiological abnormalities in the primary motor cortex (M1) contribute to bradykinesia in patients with Parkinson's disease is unclear. Bologna et al. show that M1 excitability and ...plasticity abnormalities correlate with various bradykinesia features, objectively assessed with kinematic techniques. However, additional mechanisms sensitive to dopamine levels may also play a role.
Abstract
Many neurophysiological abnormalities have been described in the primary motor cortex of patients with Parkinson's disease. However, it is unclear whether there is any relationship between them and bradykinesia, one of the cardinal motor features of the condition. In the present study we aimed to investigate whether objective measures of bradykinesia in Parkinson's disease have any relationship with neurophysiological measures in primary motor cortex as assessed by means of transcranial magnetic stimulation techniques. Twenty-two patients with Parkinson's disease and 18 healthy subjects were enrolled. Objective measurements of repetitive finger tapping (amplitude, speed and decrement) were obtained using a motion analysis system. The excitability of primary motor cortex was assessed by recording the input/output curve of the motor-evoked potentials and using a conditioning-test paradigm for the assessment of short-interval intracortical inhibition and facilitation. Plasticity-like mechanisms in primary motor cortex were indexed according to the amplitude changes in motor-evoked potentials after the paired associative stimulation protocol. Patients were assessed in two sessions, i.e. OFF and ON medication. A canonical correlation analysis was used to test for relationships between the kinematic and neurophysiological variables. Patients with Parkinson's disease tapped more slowly and with smaller amplitude than normal, and displayed decrement as tapping progressed. They also had steeper input/output curves, reduced short-interval intracortical inhibition and a reduced response to the paired associative stimulation protocol. Within the patient group, bradykinesia features correlated with the slope of the input/output curve and the after-effects of the paired associative stimulation protocol. Although dopaminergic therapy improved movement kinematics as well as neurophysiological measures, there was no relationship between them. In conclusion, neurophysiological changes in primary motor cortex relate to bradykinesia in patients with Parkinson's disease, although other mechanisms sensitive to dopamine levels must also play a role.
•This review presents the contribution of TMS to the management of dementia.•TMS can be used as a biomarker of the excitability and function of cerebral cortex in dementia.•Increasing evidence ...supports the beneficial effects of rTMS in Alzheimer’s disease-related dementias at mild/early stage.
Transcranial magnetic stimulation (TMS) is a powerful tool to probe in vivo brain circuits, as it allows to assess several cortical properties such asexcitability, plasticity and connectivity in humans. In the last 20 years, TMS has been applied to patients with dementia, enabling the identification of potential markers of thepathophysiology and predictors of cognitive decline; moreover, applied repetitively, TMS holds promise as a potential therapeutic intervention.
The objective of this paper is to present a comprehensive review of studies that have employed TMS in dementia and to discuss potential clinical applications, from the diagnosis to the treatment.
To provide a technical and theoretical framework, we first present an overview of the basic physiological mechanisms of the application of TMS to assess cortical excitability, excitation and inhibition balance, mechanisms of plasticity and cortico-cortical connectivity in the human brain. We then review the insights gained by TMS techniques into the pathophysiology and predictors of progression and response to treatment in dementias, including Alzheimer’s disease (AD)-related dementias and secondary dementias. We show that while a single TMS measure offers low specificity, the use of a panel of measures and/or neurophysiological index can support the clinical diagnosis and predict progression.
In the last part of the article, we discuss the therapeutic uses of TMS. So far, only repetitive TMS (rTMS) over the left dorsolateral prefrontal cortex and multisite rTMS associated with cognitive training have been shown to be, respectively, possibly (Level C of evidence) and probably (Level B of evidence) effective to improve cognition, apathy, memory, and language in AD patients, especially at a mild/early stage of the disease. The clinical use of this type of treatment warrants the combination of brain imaging techniques and/or electrophysiological tools to elucidate neurobiological effects of neurostimulation and to optimally tailor rTMS treatment protocols in individual patients or specific patient subgroups with dementia or mild cognitive impairment.
•Voluntary movement abnormalities can be observed in mild cognitive impairment (MCI).•Abnormal rhythm during repetitive finger movements in MCI patients relates to frontal dysfunction.•Altered ...voluntary movement may be an early motor feature in patients with cognitive decline.
Previous studies have demonstrated voluntary movement alterations as well as motor cortex excitability and plasticity changes in patients with mild cognitive impairment (MCI). To investigate the pathophysiology of movement abnormalities in MCI, we tested possible relationships between movement abnormalities and primary motor cortex alterations in patients.
Fourteen amnestic MCI (aMCI) patients and 16 healthy controls were studied. Cognitive assessment was performed using clinical scales. Finger tapping was recorded by a motion analysis system. Transcranial magnetic stimulation was used to test the input/output curve of motor evoked potentials, intracortical inhibition, and short-latency afferent inhibition. Primary motor cortex plasticity was probed by theta burst stimulation. We investigated correlations between movement abnormalities, clinical scores, and cortical neurophysiological parameters.
MCI patients showed less rhythmic movement but no other movement abnormalities. Cortical excitability measures were normal in patients, whereas plasticity was reduced. Movement rhythm abnormalities correlated with frontal dysfunction scores.
Our study in MCI patients demonstrated abnormal voluntary movement and plasticity changes, with no correlation between the two. Altered rhythm correlated with frontal dysfunction.
Our results contribute to the understanding of pathophysiological mechanisms of motor impairment in MCI.
It is well established that the primary motor cortex (M1) plays a significant role in motor learning in healthy humans. It is unclear, however, whether mechanisms of motor learning include M1 ...oscillatory activity. In this study, we aimed to test whether M1 oscillations, entrained by transcranial Alternating Current Stimulation (tACS) at motor resonant frequencies, have any effect on motor acquisition and retention during a rapid learning task, as assessed by kinematic analysis. We also tested whether the stimulation influenced the corticospinal excitability changes after motor learning. Sixteen healthy subjects were enrolled in the study. Participants performed the motor learning task in three experimental conditions: sham-tACS (baseline), β-tACS and γ-tACS. Corticospinal excitability was assessed with single-pulse TMS before the motor learning task and 5, 15, and 30 min thereafter. Motor retention was tested 30 min after the motor learning task. During training, acceleration of the practiced movement improved in the baseline condition and the enhanced performance was retained when tested 30 min later. The β-tACS delivered during training inhibited the acquisition of the motor learning task. Conversely, the γ-tACS slightly improved the acceleration of the practiced movement during training but it reduced motor retention. At the end of training, corticospinal excitability had similarly increased in the three sessions. The results are compatible with the hypothesis that entrainment of the two major motor resonant rhythms through tACS over M1 has different effects on motor learning in healthy humans. The effects, however, were unrelated to corticospinal excitability changes.
•β-tACS delivered during training inhibits the acquisition of a motor learning task.•γ-tACS slightly improved the acceleration of the practiced movement during training.•Neither β nor γ tACS influenced practice-related corticospinal excitability changes.•The effects of tACS on motor behavior were unrelated to corticospinal excitability changes.
Purpose
In the advanced stage of Parkinson disease (PD), therapeutic interventions include device-aided therapies such as continuous subcutaneous apomorphine infusion (CSAI), levodopa-carbidopa ...intestinal gel (LCIG) infusion, and deep brain stimulation (DBS). Recent evidence has underlined the general lack of randomized, blinded, head-to-head studies on device-aided therapies for advanced PD.
Methods
To better clarify the
real-world
attitude of clinicians on this matter, we conducted an international survey of forty-four experienced movement disorder specialists regarding the management of device-aided therapies in advanced PD.
Results
Our international survey showed a general agreement that nowadays, motor complications are less common compared to the past (59% agreement), that guidelines to identify candidates for device-aided therapies are currently lacking (57% agreement), and that device-aided therapies will have increased demand in the future (75% agreement).
Conclusions
We conclude that guidelines to assist clinicians and patients to choose device-aided therapies are required.
Patients with Parkinson's disease (PD) show impaired short-term potentiation (STP) mechanisms in the primary motor cortex (M1). However, the role played by this neurophysiological abnormality in ...bradykinesia pathophysiology is unknown. In this study, we used a multimodal neuromodulation approach to test whether defective STP contributes to bradykinesia. We evaluated STP by measuring motor-evoked potential facilitation during 5 Hz-repetitive transcranial magnetic stimulation (rTMS) and assessed repetitive finger tapping movements through kinematic techniques. Also, we used transcranial alternating current stimulation (tACS) to drive M1 oscillations and experimentally modulate bradykinesia. STP was assessed during tACS delivered at beta (β) and gamma (γ) frequency, and during sham-tACS. Data were compared to those recorded in a group of healthy subjects. In PD, we found that STP was impaired during sham- and γ-tACS, while it was restored during β-tACS. Importantly, the degree of STP impairment was associated with the severity of movement slowness and amplitude reduction. Moreover, β-tACS-related improvements in STP were linked to changes in movement slowness and intracortical GABA-A-ergic inhibition during stimulation, as assessed by short-interval intracortical inhibition (SICI). Patients with prominent STP amelioration had greater SICI reduction (cortical disinhibition) and less slowness worsening during β-tACS. Dopaminergic medications did not modify β-tACS effects. These data demonstrate that abnormal STP processes are involved in bradykinesia pathophysiology and return to normal levels when β oscillations increase. STP changes are likely mediated by modifications in GABA-A-ergic intracortical circuits and may represent a compensatory mechanism against β-induced bradykinesia in PD.
•Parkinson's disease patients demonstrated impaired short-term potentiation (STP).•The degree of STP impairment correlated with movement velocity and amplitude.•Beta-transcranial alternating current stimulation (tACS) restored STP in patients.•Beta-tACS-related improvements in STP were linked to changes in movement slowness.•Beta-tACS-related changes in STP were also related to GABAergic inhibitory activity.
Parkinson's disease (PD) patients have impairment of facial expressivity (hypomimia) and difficulties in interpreting the emotional facial expressions produced by others, especially for aversive ...emotions. We aimed to evaluate the ability to produce facial emotional expressions and to recognize facial emotional expressions produced by others in a group of PD patients and a group of healthy participants in order to explore the relationship between these two abilities and any differences between the two groups of participants.
Twenty non-demented, non-depressed PD patients and twenty healthy participants (HC) matched for demographic characteristics were studied. The ability of recognizing emotional facial expressions was assessed with the Ekman 60-faces test (Emotion recognition task). Participants were video-recorded while posing facial expressions of 6 primary emotions (happiness, sadness, surprise, disgust, fear and anger). The most expressive pictures for each emotion were derived from the videos. Ten healthy raters were asked to look at the pictures displayed on a computer-screen in pseudo-random fashion and to identify the emotional label in a six-forced-choice response format (Emotion expressivity task). Reaction time (RT) and accuracy of responses were recorded. At the end of each trial the participant was asked to rate his/her confidence in his/her perceived accuracy of response.
For emotion recognition, PD reported lower score than HC for Ekman total score (p<0.001), and for single emotions sub-scores happiness, fear, anger, sadness (p<0.01) and surprise (p = 0.02). In the facial emotion expressivity task, PD and HC significantly differed in the total score (p = 0.05) and in the sub-scores for happiness, sadness, anger (all p<0.001). RT and the level of confidence showed significant differences between PD and HC for the same emotions. There was a significant positive correlation between the emotion facial recognition and expressivity in both groups; the correlation was even stronger when ranking emotions from the best recognized to the worst (R = 0.75, p = 0.004).
PD patients showed difficulties in recognizing emotional facial expressions produced by others and in posing facial emotional expressions compared to healthy subjects. The linear correlation between recognition and expression in both experimental groups suggests that the two mechanisms share a common system, which could be deteriorated in patients with PD. These results open new clinical and rehabilitation perspectives.
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